This invention relates generally to novel cyclic hydroxamic acids as inhibitors of matrix metalloproteinases (MMP), TNF-xcex1 converting enzyme (TACE), aggrecanase or a combination thereof, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis; corneal, epidermal, or gastric ulceration; tumor metastasis or invasion; periodontal disease; and, bone disease.
Tumor necrosis factor-xcex1 (TNF-xcex1) has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF-xcex1 has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF-xcex1 with specific antibodies can be beneficial in a variety of circumstances including autoimmune diseases such as rheumatoid arthritis. Compounds which inhibit the production of TNF-xcex1 are of therapeutic importance for the treatment of inflammatory disorders.
This invention describes molecules that inhibit this enzyme and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrome, post ischemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, OA, RA, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV, and non-insulin dependent diabetes melitus.
Since excessive TNF-xcex1 production has been noted in several disease conditions also characterized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF-xcex1 production may also have a particular advantage in diseases where both mechanisms are involved.
Prostaglandins (PG) play a major role in the inflammation process and the inhibition of PG production has been a common target of anti-inflammatory drug discovery. Many NSAIDS have been found to prevent the production of PG by inhibiting the enzyme cyclooxygenase (COX). Among the two isoforms of COXs, COX-1 is constitutively expressed. COX-2 is an inducible isozyme associated with inflammation. Selective COX-2 inhibitor was believed to maintain the efficacy of traditional NSAIDs, which inhibit both isozymes, and produce fewer and less drastic side effects. As a result, development of selective COX-2 inhibitors has attracted major interest in the pharmaceutical industry. Because of the significant roles of PGs and TNF-xcex1 in inflammation, combined use of COX-2 and TACE inhibitors may have superior efficacy to either therapy alone in some inflammatory diseases.
WO01/70673 describes matrix metalloproteases and TNF-xcex1 inhibitors of the following formula: 
wherein ring B is a 3-13 membered non-aromatic carbocyclic or heterocyclic ring; A is a variety of groups including hydroxamic acid; Z is absent, a C3-13 carbocycle or a 5-14 membered heterocycle; Za is H, a C3-13 carbocycle or a 5-14 membered heterocycle; Ua, Xa and Ya are linkers; and, R1, R2, R2a, R2b, and R3 are a variety of groups. Compounds specifically described in WO01/70673 are not considered to be part of the present invention.
It is desirable to find new compounds with improved pharmacological characteristics compared with known MMP and/or TACE inhibitors. For example, it is preferred to find new compounds with improved MMP and/or TACE inhibitory activity and selectivity for an MMP and/or TACE versus other metalloproteases (e.g., specificity for one MMP versus another). It is also desirable and preferable to find compounds with advantageous and improved characteristics in one or more of the following categories, but are not limited to: (a) pharmaceutical properties (e.g., solubility, permeability, and amenability to sustained release formulations); (b) dosage requirements (e.g., lower dosages and/or once-daily dosing); (c) factors which decrease blood concentration peak-to-trough characteristics (e.g., clearance and/or volume of distribution); (d) factors that increase the concentration of active drug at the receptor (e.g., protein binding and volume of distribution); (e) factors that decrease the liability for clinical drugxe2x80x94drug interactions (e.g., cytochrome P450 enzyme inhibition or induction); (f) factors that decrease the potential for adverse side-effects (e.g., potential chemical or metabolic reactivity and limited CNS penetration); and, (g) factors that improve manufacturing costs or feasibility (e.g., difficulty of synthesis, number of chiral centers, chemical stability, and ease of handling).
The compounds of the present invention act as inhibitors of MPs, in particular TACE, MMPs, and/or aggrecanase. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibition of aggrecanase, TACE, and other metalloproteases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of OA and RA.
Accordingly, the present invention provides novel cyclic hydroxamic acids useful as MMP, TACE and/or aggrecanase inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
The present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method for treating inflammatory disorders, comprising: administering to a host, in need of such treatment, a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
The present invention provides a method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt or prodrug form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
The present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-xcex1 inhibitors, TNF-xcex1 sequestration agents, and methotrexate.
The present invention provides novel compounds of the present invention for use in therapy.
The present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt or prodrug form thereof, wherein B, R2, R3 and Za are defined below, are effective as MMP, TACE, and/or aggrecanase inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula (I): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring B is a 4-7 membered non-aromatic carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-3 carbonyl groups, 0-3 double bonds, and 0-2 ring heteroatoms selected from O, N, NR1, and S(O)p, provided that ring B contains other than a Sxe2x80x94S, Oxe2x80x94O, or Sxe2x80x94O bond;
R1 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)qO(CRaRa1)s-Q, (CRaRa1)qNRa(CRaRa1)s-Q, (CRaRa1)rC(O)(CRaRa1)s-Q, (CRaRa1)rC(O)xe2x80x94C2-6 alkenylene-Q, (CRaRa1)rC(O)O(CRaRa1)s-Q, (CRaRa1)qOC(O)(CRaRa1)s-Q, (CRaRa1)qOC(O)O(CRaRa1)s-Q, (CRaRa1)qOC(O)NRa(CRaRa1)s-Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)rC(O)NRa(CRaRa1)s-Q, (CRaRa1)qNRaC(O)(CRaRa1)s-Q, (CRaRa1)qNRaC(O)O(CRaRa1)s-Q (CRaRa1)qNRaC(O)NRa(CRaRa1)s-Q, (CRaRa1)rS(O)p(CRaRa1)s-Q, (CRaRa1)qNRaSO2(CRaRa1)s-Q, and (CRaRa1)rSO2NRa (CRaRa1)s-Q;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, (CRaRa1)rO(CRaRa1)s-Q, (CRaRa1)rNRa(CRaRa1)s-Q, (CRaRa1)rC(O)(CRaRa1)s-Q, (CRaRa1)rC(O)xe2x80x94C2-6 alkenylene-Q, (CRaRa1)rC(O)O(CRaRa1)s-Q, (CRaRa1)rC(O)NRaRa1, (CRaRa1)rC(O)NRa(CRaRa1)s-Q, (CRaRa1)rNRaC(O)(CRaRa1)s-Q, (CRaRa1)rNRaC(O)O(CRaRa1)s-Q, (CRaRa1)rNRaC(O)NRa(CRaRa1)s-Q, (CRaRa1)rS(O)p(CRaRa1)s-Q, and (CRaRa1)rSO2NRa (CRaRa1)s-Q;
Q is selected from H, a C3-6 carbocycle substituted with 0-3 Rd, and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rd;
R3 is selected from Q1, Cl, F, C1-6 alkylene-Q1, C2-6 alkenylene-Q1, C2-6 alkynylene-Q1, (CRaRa1)rO(CRaRa1)s-Q1, (CRaRa1)rNRa(CRaRa1)s-Q1, (CRaRa1)rNRaC(O)(CRaRa1)s-Q1, (CRaRa1)rC(O)NRa(CRaRa1)s-Q1, (CRaRa1)rC(O)(CRaRa1)s-Q1, (CRaRa1)rC(O)O(CRaRa1)s-Q1, (CRaRa12)rS(O)p(CRaRa1)s-Q1, and (CRaRa1)rSO2NRa(CRaRa1)s-Q1;
Q1 is selected from H, phenyl substituted with 0-3 Rd, naphthyl substituted with 0-3 Rd and a 5-10 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rd;
Za is selected from the group: 
X is S, SO, SO2, O, or NR14;
Y is N or CR17;
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1; and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
alternatively, when R13 and R13a are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
R14, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
R15 and R16, at each occurrence, are independently selected from H, Rc1, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
alternatively, when R15 and R16 are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
alternatively, when R15 and R16 are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
R17 is selected from H, Cl, F, and C1-4 alkyl;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
Ra1, at each occurrence, is independently selected from H and C1-4 alkyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, phenyl, and benzyl;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)ORa, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, xe2x80x94CN, NO2, NRaRa1, C(O)Ra, C(O)ORa, C(O)NRaRa1, RaNC(O)NRaRa1, OC(O)NRaRa1, RaNC(O)O, S(O)2NRaRa1, NRaS(O)2Ra2, NRaS(O)2NRaRa1, OS(O)2NRaRa1, NRaS(O)2Ra2, S(O)pRa2, CF3, OCF3, CF2CF3, C3-10 carbocycle, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p;
p, at each occurrence, is selected from 0, 1, and 2;
q, at each occurrence, is selected from 1, 2, 3, and 4;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and,
s, at each occurrence, is selected from 0, 1, 2, 3, and 4.
[2] In a preferred embodiment, the present invention provides a novel compound of formula (I), wherein;
ring B is a 5-6 membered non-aromatic carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 ring heteroatoms selected from O, N, and NR1, provided that ring B contains other than a Oxe2x80x94O bond;
R1 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenylene-Q, C(O)O(CRaRa1)s-Q, C(O)NRaRa1, C(O)NRa(CRaRa1)s-Q, and S(O)p(CRaRa1)s-Q;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenylene-Q, C(O)O(CRaRa1)s-Q, C(O)NRa(CRaRa1)s-Q, and S(O)p(CRaRa1)s-Q;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-3 Rd, and a heterocycle substituted with 0-2 Rd, wherein the heterocycle is selected from pyridyl, quinolinyl, thiazolyl, furanyl, tetrahydrofuranyl, imidazolyl, isoxazolyl, pyranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl;
R3 is selected from Q1, Cl, F, C1-4 alkylene-Q1, C2-4 alkenylene-Q1, and C2-4 alkynylene-Q1;
Q1 is selected from H and phenyl;
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, and phenyl substituted with 0-3 Rc1;
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, C3-6 cycloalkyl substituted with 0-2 Rc1, phenyl substituted with 0-3 Rc1, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p and substituted with 0-3 Rc1;
alternatively, when R13 and R13a are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached they form a 5-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
R14, at each occurrence, is independently selected from H, C1-4 alkyl, and benzyl;
R15 and R16, at each occurrence, are independently selected from H, Rc1, C1-4 alkyl substituted with 0-3 Rc1, and phenyl substituted with 0-3 Rc1;
alternatively, when R15 and R16 are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
alternatively, when R15 and R16 are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-1 Rc1;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, and benzyl;
Ra2, at each occurrence, is independently selected from C1-4 alkyl, and benzyl;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2; and,
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, and phenyl.
[3] In another preferred embodiment, the present invention provides a novel compound of formula (I), wherein;
ring B is a 5-6 membered non-aromatic carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and 0-1 ring heteroatoms selected from O, N, and NR1;
R1 is selected from Q, C1-6 alkylene-Q, C2-4 alkenylene-Q, C2-4 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenyl, C(O)O(CRaRa1)s-Q, C(O)NRa-Q, and S(O)p(CRaRa1)s-Q;
R2 is selected from Q, C1-4 alkylene-Q, C2-4 alkenylene-Q, C2-4 alkynylene-Q, C(O)-Q, C(O)xe2x80x94C2-6 alkenyl, C(O)O-Q, C(O)NRa-Q, and S(O)p-Q;
Q is selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, and phenyl substituted with 0-2 Rd;
R3 is H;
X is S, SO, SO2 or O;
Y is N;
R11 and R12, at each occurrence, are independently selected from H, Rc, and C1-4 alkyl substituted with 0-3 Rc1;
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, C3-6 cycloalkyl substituted with 0-2 Rc1, phenyl substituted with 0-3 Rc1, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-2 heteroatoms selected from the group consisting of N, O, and S(O)p;
alternatively, when R13 and R13a are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 double bonds, and 0-1 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
R15 and R16, at each occurrence, are independently selected from H, Rc1, and C1-4 alkyl substituted with 0-3 Rc1;
alternatively, when R15 and R16 are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 6 membered aromatic ring substituted with 0-2 Rc1;
alternatively, when R15 and R16 are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3-6 membered cycloalkyl;
Ra, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Ra1, at each occurrence, is independently selected from H, CH3, and CH2CH3; and,
Ra2, at each occurrence, is independently selected from CH3, and CH2CH3.
[4] In another preferred embodiment, the present invention provides a novel compound of formula (II): 
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
ring B is selected from the group: 
R1 is selected from H, methyl, isopropyl, butyl, isobutyl, neopentyl, allyl, 3-butenyl, 2-propynyl, 2-butynyl, 3-butynyl, acetyl, t-butylcarbonyl, 4-pentenoyl, t-butoxycarbonyl, methoxycarbonyl, methylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, phenyl, 4-F-phenyl, 4-methoxy-phenyl, cyclopropylmethyl, cyclopentyl, and tetrahydro-2H-pyran-4-yl; and,
Za is selected from the group: 
[5] In another preferred embodiment, the present invention provides a novel compound of formula (I), wherein;
Za is selected from the group: 
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1; and,
R14, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl.
[6] In a preferred embodiment, the present invention provides a novel compound of formula (I), wherein;
Za is selected from the group: 
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, and phenyl substituted with 0-3 Rc1;
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, C3-6 cycloalkyl substituted with 0-2 Rc1, phenyl substituted with 0-3 Rc1, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1; and,
R14, at each occurrence, is independently selected from H, C1-4 alkyl, and benzyl.
[7] In another preferred embodiment, the present invention provides a novel compound of formula (II), wherein;
ring B is selected from the group: 
R1 is selected from H, methyl, isopropyl, butyl, isobutyl, neopentyl, allyl, 3-butenyl, 2-propynyl, 2-butynyl, 3-butynyl, acetyl, t-butylcarbonyl, 4-pentenoyl, t-butoxycarbonyl, methoxycarbonyl, methylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, phenyl, 4-F-phenyl, 4-methoxy-phenyl, cyclopropylmethyl, cyclopentyl, and tetrahydro-2H-pyran-4-yl; and,
Za is selected from the group: 
[8] In another preferred embodiment, the present invention provides a compound selected from the group:
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(methylsulfonyl)-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-methyl-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-1-acetyl-N-hydroxy-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-(propylsulfonyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(isopropylsulfonyl)-4-[(4-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-benzimidazol-1-yl) methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(3-butenyl)-N-hydroxy-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-methyl-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-propyl-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(3-butenyl)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-(propylsulfonyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(butylsulfonyl)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-(isopropylsulfonyl)-3-pyrrolidinecarboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzamide;
(3S,4S)-N-hydroxy-1-isobutyl-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(2-propynyl)-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-1-(3-butenyl)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3S,4S)-N-hydroxy-1-(propylsulfonyl)-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(isopropylsulfonyl)-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-1-(butylsulfonyl)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-1-acetyl-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(4-pentenoyl)-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isobutyl-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-neopentyl-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-pyrrolidinecarboxamide;
cis-N-{-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzamide;
(3R,4S)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]tetrahydro-3-furancarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-(2-butynyl)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide;
cis-4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]-N-{2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
tert-butyl (3S,4S)-3-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-isobutyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxy-1-neopentyl-3-pyrrolidinecarboxamide;
4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}-N-cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-[(4-{[2-(difluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxytetrahydro-3-furancarboxamide;
4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
4-[(2-cyclobutyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2-cyclobutyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-{[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]methyl}benzamide;
(3R,4R)-4-[(4-{[2-(fluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
4-{[2-(fluoromethyl)-1H-benzimidazol-1-yl]methyl}-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-[(4-{[2-(1-fluoro-1-methylethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
4-{[2-(1-fluoro-1-methylethyl)-1H-benzimidazol-1-yl]methyl}-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3S,4R)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-3-({4-[(2-chloro-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methoxy-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[4-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)benzoyl]amino}-1-pyrrolidinecarboxylate;
(3R,4R)-4-({4-[(2-chloro-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-{[4-(1H-imidazo[4,5-b]pyridin-1-ylmethyl)benzoyl]amino}-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-5-nitro-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-6-nitro-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-({4-[(5-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-({4-[(6-chloro-2-methyl-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,6S)-6-[(hydroxyamino)carbonyl]-3-cyclohexen-1-yl}benzamide;
4-[(2-cyclobutyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,6S)-6-[(hydroxyamino)carbonyl]-3-cyclohexen-1-yl}benzamide;
N-{(1R,6S)-6-[(hydroxyamino)carbonyl]-3-cyclohexen-1-yl}-4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclohexyl}-4-[(2-isopropyl-1H-benzimidazol-1-yl)methyl]benzamide;
4-[(2-cyclopropyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclohexyl}benzamide;
4-[(2-cyclobutyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclohexyl}benzamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclohexyl}-4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzamide;
4-[(2-tert-butyl-1H-benzimidazol-1-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclohexyl}benzamide;
tert-butyl (3S,4R)-3-[(hydroxyamino)carbonyl]-4-[(4-{[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-piperidinecarboxylate;
(3S,4R)-N-hydroxy-4-[(4-{[2-(1-methylcyclopropyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-3-piperidinecarboxamide;
tert-butyl (3S,4S)-4-[(hydroxyamino)carbonyl]-3-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-1-piperidinecarboxylate;
(3S,4S)-N-hydroxy-3-[(4-{[2-(trifluoromethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]-4-piperidinecarboxamide;
(3R,4R)-4-({4-[(2-(1,1-difluoro-ethyl)-1H-benzimidazol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridin-1-yl]methyl}benzoyl)amino]-tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(methoxymethyl)-1H-benzimidazol-1-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-({4-[(1,2-dimethyl-1H-1indol-3-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,2-dimethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-methyl-1H-indol-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-methyl-1H-indol-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-1H-indol-1-yl)methyl]benzamide;
tert-butyl (3S,4S)-3-({4-[(2,3-dimethyl-1H-indol-1-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-isopropyl-1H-indol-1-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1H-indol-1-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2,3-dimethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3R,4R)-4-({4-[(2,3-dimethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-1H-indol-1-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-ethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2-ethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydrofuran-3-carboxamide;
(3R,4S)-4-({4-[(2,3-dimethyl-1H-indol-1-yl)methyl]benzoyl}amino)-N-hydroxytetrahydrofuran-3-carboxamide;
(3R,4R)-4-({4-[(2-ethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2-ethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydrofuran-3-carboxamide;
(3R,4S)-N-hydroxy-4 [(4-{[2-(trifluoromethyl)-1H-indol-1-yl]methyl}benzoyl)amino]tetrahydrofuran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(3-methyl-1H-indol-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-N-hydroxy-4-({4-[(3-methyl-1H-indol-1-yl)methyl]benzoyl}amino)tetrahydrofuran-3-carboxamide;
(3R,4R)-4-({4-[(1,2-dimethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
N-cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(3-methyl-1H-indol-1-yl)methyl]benzamide;
(3R,4S)-4-({4-[(1,2-dimethyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydrofuran-3-carboxamide;
(3R,4S)-4-({4-[(2-ethyl-1-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydrofuran-3-carboxamide;
(3R,4R)-4-({4-[(2-ethyl-1-methyl-1H-indol-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-methyl-1-benzofuran-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-1-benzofuran-3-yl)methyl]benzoyl}amino)pyrrolidine-1-carboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-1-benzofuran-3-yl)methyl]benzoyl}amino)pyrrolidine-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-isopropyl-1-benzofuran-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-isopropyl-1-benzofuran-3-yl)methyl]benzoyl}amino)pyrrolidine-1-carboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-1-benzofuran-3-yl)methyl]benzoyl}amino)pyrrolidine-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-tert-butylimidazo[1,2-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-isopropylimidazo[1,2-a]pyridin-3-yl)methyl]benzamide;
(3R,4R)-N-hydroxy-4-({4-[(2-isopropylimidazo[1,2-a]pyridin-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
4-[(2-tert-butylimidazo[1,2-a]pyridin-3-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2-cyclobutylimidazo[1,2-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-{[2-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl]methyl}benzamide;
4-[(2-cyclobutylimidazo[1,2-a]pyridin-3-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2-cyclopropylimidazo[1,2-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-ethylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-(1-hydroxy-1-methylethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-tert-butylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-cyclopropylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-cyclobutylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
4-[(2-cyclobutylpyrazolo[1,5-a]pyridin-3-yl)methyl]-N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-N-hydroxy-4-({4-[(2-phenylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-cyclopentylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-tetrahydro-2H-pyran-4-ylpyrazolo[1,5-a]pyridin-3-yl)methyl]benzoylamino)tetrahydro-2H-pyran-3-carboxamide;
N-{(1R,2S)-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-{[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-[(4-{[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]pyrrolidine-1-carboxylate;
(3S,4S)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]pyrrolidine-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[7-methyl-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-({4-[(1-methylimidazo[1,5-a]pyridin-3-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[1-(trifluoromethyl)imidazo[1,5-a]pyridin-3-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[3-(trifluoromethyl)imidazo[1,5-a]pyridin-1-yl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide; and,
(3R,4R)-N-hydroxy-4-({4-[(3-methylimidazo[1,5-a]pyridin-1-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
or a pharmaceutically acceptable salt form thereof.
[9] In another preferred embodiment, the present invention provides a novel compound of formula I, wherein;
Za is 
X is S, SO, SO2, O, or NR14;
Y is N or CR17;
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
R14, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, and benzyl;
R15 and R16, at each occurrence, are independently selected from H, Rc1, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1;
alternatively, when R15 and R16 are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
alternatively, when R15 and R16 are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p; this ring is substituted with 0-2 Rc1; and,
R17 is selected from H, Cl, F, and C1-4 alkyl.
[10] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein;
Za is 
X is S, SO, SO2, O, or NR14;
Y is N or CR17;
R11 and R12, at each occurrence, are independently selected from H. Rc, C1-4 alkyl substituted with 0-3 Rc1, and phenyl substituted with 0-3 Rc1;
R14, at each occurrence, is independently selected from H, C1-4 alkyl, and benzyl;
R15 and R16, at each occurrence, are independently selected from H, Rc1, C1-4 alkyl substituted with 0-3 Rc1, and phenyl;
alternatively, when R15 and R16 are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1;
alternatively, when R15 and R16 are attached to the same carbon atom, together with the carbon atom to which they are attached they form a 3-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p; this ring is substituted with 0-1 Rc1; and,
R17 is selected from H, Cl, F, and C1-4 alkyl.
[11] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein;
ring B is selected from the group: 
R1 is selected from H, methyl, isopropyl, butyl, isobutyl, neopentyl, allyl, 3-butenyl, 2-propynyl, 2-butynyl, 3-butynyl, acetyl, t-butylcarbonyl, 4-pentenoyl, t-butoxycarbonyl, methoxycarbonyl, methylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, phenyl, 4-F-phenyl, 4-methoxy-phenyl, cyclopropylmethyl, cyclopentyl, and tetrahydro-2H-pyran-4-yl; and,
Za is selected from the group: 
[12] In another preferred embodiment, the present invention provides a compound selected from the group:
tert-butyl (3S,4S)-3-{[4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoyl]amino}-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-4-{[4-(2,3-dihydro-4H-1,4-benzothiazin-4-ylmethyl)benzoyl]amino}-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
tert-butyl (3S,4S)-3-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-isobutyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-methyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-(isopropylsulfonyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-acetyl-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2,2-dimethylpropanoyl)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-phenyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-1(4-fluorophenyl)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-(4-methoxyphenyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(cyclopropylmethyl)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-1-cyclopentyl-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-tetrahydro-2H-pyran-4-yl-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-neopentyl-3-pyrrolidinecarboxamide;
4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-cis-{2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4S)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-4-({4-[(1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-3-({4-[(2,2-dimethyl-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-({4-[(2,2-dimethyl-1-oxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
tert-butyl (3S,4S)-3-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-isopropyl-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-isobutyl-3-pyrrolidinecarboxamide;
(3S,4S)-1-butyl-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxy-1-neopentyl-3-pyrrolidinecarboxamide;
(3R,4R)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
4-[(2,2-dimethyl-1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl)methyl]-N-cis-{2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
tert-butyl (3S,4S)-3-{[4-(2,3-dihydro-4H-1,4-benzoxazin-4-ylmethyl)benzoyl]amino}-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate; and,
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-{[4-(10H-phenoxazin-10-ylmethyl)benzoyl]amino}-1-pyrrolidinecarboxylate;
or a pharmaceutically acceptable salt form thereof.
[13] In another preferred embodiment, the present invention provides a novel compound of formula I, wherein;
Za is 
R11 and R12, at each occurrence, are independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1; and
R13 and R13a, at each occurrence, is independently selected from H, Rc, C1-6 alkyl substituted with 0-3 Rc1, C3-10 carbocycle substituted with 0-3 Rc1, and a 5-14 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1; and,
alternatively, when R13 and R13a are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-7 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-2 carbonyl groups, 0-3 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1.
[14] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein;
Za is 
R13 and R13a, at each occurrence, are independently selected from H, Rc, C1-4 alkyl substituted with 0-3 Rc1, C3-6 cycloalkyl substituted with 0-2 Rc1, phenyl substituted with 0-3 Rc1, and a 5-6 membered heterocycle consisting of: carbon atoms and 1-4 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-3 Rc1; and,
alternatively, when R13 and R13a are attached to adjacent carbon atoms, together with the carbon atoms to which they are attached, they form a 5-6 membered carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 heteroatoms selected from the group consisting of N, O, and S(O)p, and substituted with 0-2 Rc1.
[15] In another preferred embodiment, the present invention provides a novel compound of formula II, wherein;
ring B is selected from the group: 
R1 is selected from H, methyl, isopropyl, butyl, isobutyl, neopentyl, allyl, 3-butenyl, 2-propynyl, 2-butynyl, 3-butynyl, acetyl, t-butylcarbonyl, 4-pentenoyl, t-butoxycarbonyl, methoxycarbonyl, methylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, phenyl, 4-F-phenyl, 4-methoxy-phenyl, cyclopropylmethyl, cyclopentyl, and tetrahydro-2H-pyran-4-yl; and,
Za is selected from the group: 
[16] In another preferred embodiment, the present invention provides a compound selected from the group:
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isobutyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-butyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-methyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-allyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(cyclopropylmethyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-cyclopentyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-neopentyl-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-tetrahydro-2H-pyran-4-yl-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-phenyl-3-pyrrolidinecarboxamide;
(3S,4S)-1-(4-fluorophenyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(methoxyphenyl)-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-acetyl-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2,2-dimethylpropanoyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-(isopropylsulfonyl)-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(butylsulfonyl)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide; methyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3R,4S)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)tetrtahydro-3-furancarboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
N-cis-{2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-methyl-4-quinolinyl)methyl]benzamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-1-isopropyl-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3S,4S)-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-1-methyl-3-pyrrolidinecarboxamide;
(3S,4S)-1-cyclopentyl-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxamide;
(3R,4R)-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino) tetrahydro-2H-pyran-3-carboxamide;
N-cis-{2-[(hydroxyamino)carbonyl]cyclopentyl}-4-[(2-isopropyl-4-quinolinyl)methyl]benzamide;
(3R,4S)-N-hydroxy-4-({4-[(2-isopropyl-4-quinolinyl)methyl]benzoyl}amino)tetrtahydro-3-furancarboxamide;
tert-butyl (3S,4S)-3-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-4-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
(3S,4S)-4-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3S,4S)-4-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3S,4S)-1-(2-butynyl)-4-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-3-pyrrolidinecarboxamide;
(3R,4R)-4-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
4-[(2-ethyl-4-quinolinyl)methyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-benzamide;
(3R,4S)-4-({4-[(2-ethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrtahydro-3-furancarboxamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2-(trifluoromethyl)-4-quinolinyl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3R,4R)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}-4-{[2-(trifluoromethyl)-4-quinolinyl]methyl}benzamide;
tert-butyl (3S,4S)-3-[(hydroxyamino)carbonyl]-4-({4-[(2,3-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-1-pyrrolidinecarboxylate;
(3R,4R)-4-({4-[(2,3-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
4-[(2,3-dimethyl-4-quinolinyl)methyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3S,4S)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3R,4S)-N-hydroxy-4-[(4-{[2-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]-tetrahydro-3-furancarboxamide;
(3S,4S)-4-({4-[(2,3-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxy-1-(2-propynyl)-3-pyrrolidinecarboxamide;
(3R,4S)-N-hydroxy-4-({4-[(2,3-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-tetrahydro-3-furancarboxamide;
(3R,4R)-4-[(4-{[2-(dimethylamino)-4-quinolinyl]methyl}benzoyl)amino]-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2-cyclopropyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-4-({4-[(2-cyclopropyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-{[4-(1,3-dihydrofuro[3,4-b]quinolin-9-ylmethyl)benzoyl]amino}-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-4-{[4-(1,3-dihydrofuro[3,4-b]quinolin-9-ylmethyl)benzoyl]amino}-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
tert-butyl (3S,4S)-4-({4-[(2,8-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-3-[(hydroxyamino)carbonyl]-1-pyrrolidinecarboxylate;
4-[(2,8-dimethyl-4-quinolinyl)methyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-4-({4-[(2,8-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(2,8-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-N-hydroxy-4-[(4-{[2-methyl-8-(trifluoromethyl)-4-quinolinyl]methyl}benzoyl)amino]tetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(8-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(8-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-4-({4-[(3-ethyl-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-([4-[(3-ethyl-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
4-[(3-ethyl-2-methyl-4-quinolinyl)methyl]-N-[cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4S)-4-({4-[(2,6-dimethyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
4-[(2,6-dimethyl-4-quinolinyl)methyl]-N-{cis-2-[(hydroxyamino)carbonyl]cyclopentyl}benzamide;
(3R,4R)-N-hydroxy-4-({4-[(2,6-dimethyl-4-quinolinyl)methyl]benzoyl}amino) tetrahydro-2H-pyran-3-carboxamide;
(3R,4S)-4-({4-[(6-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-3-furancarboxamide;
(3R,4R)-4-({4-[(6-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(6-fluoro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(7-chloro-2-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-{[4-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylmethyl)benzoyl]amino}-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-{[4-(2,3-dihydrofuro[2,3-b]quinolin-4-ylmethyl)benzoyl]amino}-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-{[4-(acridin-9-ylmethyl)benzoyl]amino}-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(3-methyl-4-quinolinyl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide;
(3R,4R)-4-({4-[(2-bromoquinolin-4-yl)methyl]benzoyl}amino)-N-hydroxytetrahydro-2H-pyran-3-carboxamide; and,
(3R,4R)-N-hydroxy-4-({4-[(2-morpholin-4-ylquinolin-4-yl)methyl]benzoyl}amino)tetrahydro-2H-pyran-3-carboxamide;
or a pharmaceutically acceptable salt form thereof.
In another preferred embodiment, the present invention provides a novel compound, wherein;
ring B is a 5-6 membered non-aromatic carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-2 double bonds, and 0-2 ring heteroatoms selected from O, N, and NR1, provided that ring B contains other than a Oxe2x80x94O bond.
In another preferred embodiment, the present invention provides a novel compound, wherein;
ring B is a 5-6 membered non-aromatic carbocyclic or heterocyclic ring consisting of: carbon atoms, 0-1 carbonyl groups, 0-1 double bonds, and 0-1 ring heteroatoms selected from O, N, and NR1.
In another preferred embodiment, the present invention provides a novel compound, wherein;
ring B is selected from the group: 
In another preferred embodiment, the present invention provides a novel compound, wherein;
R1 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenylene-Q, C(O)O(CRaRa1)s-Q, C(O)NRaRa1, C(O)NRa(CRaRa1)s-Q, and S(O)p(CRaRa1)s-Q.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R1 is selected from Q, C1-6 alkylene-Q, C2-4 alkenylene-Q, C2-4 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenyl, C(O)O(CRaRa1)s-Q, C(O)NRa-Q, and S(O)p(CRaRa1)s-Q;
In another preferred embodiment, the present invention provides a novel compound, wherein;
R1 is selected from H, methyl, isopropyl, butyl, isobutyl, neopentyl, allyl, 3-butenyl, 2-propynyl, 2-butynyl, 3-butynyl, acetyl, t-butylcarbonyl, 4-pentenoyl, t-butoxycarbonyl, methoxycarbonyl, methylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, phenyl, 4-F-phenyl, 4-methoxy-phenyl, cyclopropylmethyl, cyclopentyl, and tetrahydro-2H-pyran-4-yl.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R2 is selected from Q, C1-6 alkylene-Q, C2-6 alkenylene-Q, C2-6 alkynylene-Q, C(O)(CRaRa1)s-Q, C(O)xe2x80x94C2-6 alkenylene-Q, C(O)O(CRaRa1)s-Q, C(O)NRa(CRaRa1)s-Q, and S(O)p(CRaRa1)s-Q.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R2 is selected from Q, C1-4 alkylene-Q, C2-4 alkenylene-Q, C2-4 alkynylene-Q, C(O)-Q, C(O)xe2x80x94C2-6 alkenyl, C(O)O-Q, C(O)NRa-Q, and S(O)p-Q.
In another preferred embodiment, the present invention provides a novel compound, wherein;
Q is selected from H, cyclopropyl substituted with 0-1 Rd, cyclobutyl substituted with 0-1 Rd, cyclopentyl substituted with 0-1 Rd, cyclohexyl substituted with 0-1 Rd, phenyl substituted with 0-3 Rd and a heterocycle substituted with 0-2 Rd, wherein the heterocycle is selected from pyridyl, quinolinyl, thiazolyl, furanyl, tetrahydrofuranyl, imidazolyl, isoxazolyl, pyranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, and pyrrolidinyl.
In another preferred embodiment, the present invention provides a novel compound, wherein;
Q is selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyran-4-yl, and phenyl substituted with 0-2 Rd.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R3 is selected from Q1, Cl, F, C1-4 alkylene-Q1, C2-4 alkenylene-Q1, and C2-4 alkynylene-Q1; and
Q1 is selected from H and phenyl.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R3 is H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, and benzyl.
In another preferred embodiment, the present invention provides a novel compound, wherein;
R3 is H and C1-4 alkyl.
In another preferred embodiment, the present invention provides a novel compound, wherein;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2.
In another preferred embodiment, the present invention provides a novel compound, wherein;
Rc1, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, OCF3, CF2CF3, CH2F, and CHF2.
In another preferred embodiment, the present invention provides a novel compound, wherein;
Rd, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, xe2x95x90O, NRaRa1, C(O)Ra, C(O)NRaRa1, S(O)2NRaRa1, S(O)pRa2, CF3, and phenyl.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method comprising: administering a compound of the present invention or a pharmaceutically acceptable salt form thereof in an amount effective to treat a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
In another embodiment, the present invention provides a novel method of treating a disease or condition, wherein the disease or condition is selected from acute infection, acute phase response, age related macular degeneration, alcoholic liver disease, allergy, allergic asthma, anorexia, aneurism, aortic aneurism, asthma, atherosclerosis, atopic dermatitis, autoimmune disease, autoimmune hepatitis, Bechet""s disease, cachexia, calcium pyrophosphate dihydrate deposition disease, cardiovascular effects, chronic fatigue syndrome, chronic obstruction pulmonary disease, coagulation, congestive heart failure, corneal ulceration, Crohn""s disease, enteropathic arthropathy, Felty""s syndrome, fever, fibromyalgia syndrome, fibrotic disease, gingivitis, glucocorticoid withdrawal syndrome, gout, graft versus host disease, hemorrhage, HIV infection, hyperoxic alveolar injury, infectious arthritis, inflammation, intermittent hydrarthrosis, Lyme disease, meningitis, multiple sclerosis, myasthenia gravis, mycobacterial infection, neovascular glaucoma, osteoarthritis, pelvic inflammatory disease, periodontitis, polymyositis/dermatomyositis, post-ischaemic reperfusion injury, post-radiation asthenia, psoriasis, psoriatic arthritis, pulmonary emphysema, pydoderma gangrenosum, relapsing polychondritis, Reiter""s syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, sepsis syndrome, Still""s disease, shock, Sjogren""s syndrome, skin inflammatory diseases, solid tumor growth and tumor invasion by secondary metastases, spondylitis, stroke, systemic lupus erythematosus, ulcerative colitis, uveitis, vasculitis, and Wegener""s granulomatosis.
In another embodiment, the present invention provides novel compounds of the present invention for use in therapy.
In another embodiment, the present invention provides the use of novel compounds of the present invention for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TACE, aggrecanase, or a combination thereof.
In another embodiment, the present invention provides a method for treating inflammatory disorders, comprising: administering, to a host in need of such treatment, a therapeutically effective amount of one of the compounds of the present invention, in combination with one or more additional anti-inflammatory agents selected from selective COX-2 inhibitors, interleukin-1 antagonists, dihydroorotate synthase inhibitors, p38 MAP kinase inhibitors, TNF-xcex1 inhibitors, TNF-xcex1 sequestration agents, and methotrexate.
In another embodiment, the present invention provides a novel article of manufacture, comprising:
(a) a first container;
(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
(c) a package insert stating that the pharmaceutical composition can be used for the treatment of an inflammatory disorder.
In another embodiment, the present invention provides a novel article of manufacture, comprising:
(a) a first container;
(b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising: a compound of the present invention or a pharmaceutically acceptable salt form thereof; and,
(c) a package insert stating that the pharmaceutical composition can be used in combination with a second therapeutic agent to treat an inflammatory disorder.
In another preferred embodiment, the present invention provides a novel article of manufacture, further comprising:
(d) a second container;
wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container.
This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. It is also understood that each and every element of any embodiment is intended to be a separate specific embodiment. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. C is and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
Preferably, the molecular weight of compounds of the present invention is less than about 500, 550, 600, 650, 700, 750, 800, 850, or 900 grams per mole. More preferably, the molecular weight is less than about 850 grams per mole. Even more preferably, the molecular weight is less than about 750 grams per mole. Still more preferably, the molecular weight is less than about 700 grams per mole.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
The term xe2x80x9cindependently selected fromxe2x80x9d, xe2x80x9cindependently, at each occurrencexe2x80x9d or similar language, means that the labeled R substitution group may appear more than once and that each appearance may be a different atom or molecule found in the definition of that labeled R substitution group. Thus if the labeled Ra substitution group appear four times in a given permutation of Formula I, then each of those labeled Ra substitution groups may be a different group falling in the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl (or alkylene), is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl (or alkenylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C1-0alkenyl groups. xe2x80x9cAlkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbonxe2x80x94carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl (or alkynylene), is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C1-0alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic groupxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic groupxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4H-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl, 1,1-dioxido-2,3-dihydro-4H-1,4-benzothiazin-4-yl, 1,1-dioxido-3,4-dihydro-2H-1-benzothiopyran-4-yl, 3,4-dihydro-2H-chromen-4-yl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, and pyrazolo[1,5-a]pyridinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a desired metalloprotease in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of the desired target) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased anti-inflammatory effect, or some other beneficial effect of the combination compared with the individual components.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. A general description of the synthetic methods for preparing the compounds of the present invention can be found in WO01/70673, which is hereby incorporated herein by reference.